In the past few decades, chemists have been able to precisely modify molecular structures to increase the diversity and complexity of molecular backbones through molecular backbone editing strategies (e.g., ring expansion, ring contraction, and single atom exchange) (Fig. 1A), and have successfully achieved backbone editing of indole, indazole, pyrimidine, and quinoline systems, and can also be directly applied to backbone transitions and isotope labeling in medicinal chemistry. Pyridine and its derivatives are widely used in medicine, dyes, pesticides and other fields, especially in the field of pesticides, which can be used as herbicides such as paraquat and insecticides such as chlorpyrifos, so pyridine has become the main candidate for skeleton editing. However, although the preparation of benzene from pyridine is a potential exchange reaction, the process is extremely challenging because the chemistry of benzene and electron-deficient pyridine heterocycles is significantly different, so chemists apply different pyridine functionalizations to obtain previously difficult to prepare benzene by N-C substitution. In 1978, Kost and Sagitullin et al. rearranged 2-methylpyridine 1 to aniline 2 by Zincke intermediate 3 under alkaline conditions (Figure 1B). Subsequently, Kano and Morofuji et al. made improvements to the method. Recently, Studer et al. reported a diatomic substitution method using cycloaddition chemistry in which dihydropyridine 7 undergoes a Diels-Alder reaction, followed by the release of a C=N unit by an inverse cycloaddition reaction and the resulting benzene molecule 8 (Nat. Chem., 2024, 16, 741, click to read more).
Figure 1. Background and work in this paper. Image source: Chem
In 1964, Schmerling and Toekelt et al. converted pyridine to benzoic acid by a nucleophilic addition ring-open-closed-loop (ANRORC) process, but this process had a very low yield ( <6%), and the reaction conditions are harsh. Recently, Professor Michael F. Greaney's research group at the University of Manchester in United Kingdom has developed a general method for converting pyridine into benzene by N→C substitution using the ANRORC process, which can obtain a variety of benzene derivatives in a one-pot method with good yields, and at the same time realize the post-modification of bioactive molecules. The specific process is as follows (Figure 1C): first, pyridine compound 11 is trifluoromethanesulfonylated, intermolecular addition with a carbon nucleophile to obtain an intermediate 12, 12 is obtained by ring opening to obtain a carbon-Zincke analogue 13, and then a carbon ring is closed to obtain a carbon ring 14, possibly by elimination to obtain the desired product benzene 15, depending on the structure of the nucleophile. The results were published in Chem.
Figure 2. ANRORC Initial Exploration. Image source: Chem
First, the authors reacted 2-phenypyridine or 4-phenypyridine with Tf2O at -78 °C, then added diethyl malonate (nucleophile)/Et3N and raised to room temperature for the reaction, and the results showed that 2-phenylpyridine yielded a mixture of two simple adducts17 and 18 (Figure 2A), of which the undesirable 4-substituted dihydropyridine 18 was the main product; 4-Phenylpyridine, on the other hand, successfully underwent the required ANRORC reaction with a yield of 52% to obtain a carbon ring product20 (Fig. 2B), which could be purified by column chromatography and confirmed by X-ray diffraction analysis. Further optimization showed that when the ratio of trifluoromethanesulfonic anhydride, malonate and Et3N (relative to pyridine substrate) was 1.2:1.2:2.5, the yield could be increased to 83%. Subsequently, the authors investigated the aromatization step, where the separated carbon ring compounds 20 and Et3N were heated to reflux and a small amount of paraben 21 was observed (Figure 3), with a significant increase in yield (80%) when heated at 140 °C in DMF. It is worth mentioning that these two processes can be operated by the one-pot method, that is, after the completion of the ANRORC process, the solvent is changed to DMF and heated for 3 h, and the benzoate 21 can be obtained with a yield of 50%, and further optimization shows that the use of K2CO3 in the second step of the one-pot method is more effective, and benzoic acid 21 is obtained with a total yield of 71%.
Figure 3. Reaction conditions are optimized. Image source: Chem
Under optimal conditions, the authors investigated the substrate range of pyridine (Fig. 4) and showed that a variety of 4-arylpyridine (21-30), 3,4-disubstituted pyridine (34-38), 4-tertaryl-substituted pyridine (39-42) and even bioactive molecules (43,45) were compatible with the reaction, and the corresponding benzoate was obtained in moderate to good yields, although the 4-electron-withdrawing group substituted pyridine (31-33) was less active in the ANRORC reaction. The corresponding aromatic hydrocarbon product is obtained at a low yield, but a large amount of starting pyridine substrate is left. In addition, the reaction can tolerate a variety of functional groups, such as: methoxy (22), trifluoromethyl (23), aldehyde (24, 36), cyano (25), halogen atoms (27, 34), thiophene (28), tertiary amine substituents (30, 38), alkyne (37), etc. It is worth mentioning that 4,4'-bipyridine can also be selectively converted to 4-arylpyridine 29, in which case trifluoromethanesulfonylation of one of the rings is inactivated using a 2-chlorosubstituent.
Figure 4. Pyridine substrate range. Image source: Chem
Next, the authors investigated the reaction effect of ketone ester substitutes as nucleophiles, and the results showed that both ethyl acetoacetate and ethyl benzoylacetate were effective in ANRORC reactions and aromatization processes, yielding the corresponding products in 36-95% yields (Figure 5A), and that the aromatization step for ketone elimination (which can be performed at room temperature) was much easier than that of malonate. Similarly, acetylacetone is converted to the desired acetophenone derivatives at 60-94% yield when heated to room temperature after trifluoromethanesulfonation (Figure 5B). In addition, the use of these ketone esters provides insight into the elimination mechanisms that enable aromatization. First, the by-product N-trifluoromethanesulfonylbenzamide can be isolated from the preparation of 39 using ethyl benzoacetate. Second, the reaction of ethyl acetoacetate with 4-tert-butylpyridine at room temperature showed that 50% conversion to N-C bond exchange product 39 (Figure 5C) and 50% conversion to ANRORC product 52, 52 being a single diastereomer (purified and X-ray characterized) and trifluoromethanesulfonamide and ketone in anti-configuration, these results suggest that aromatization proceeds with a SYN-elimination mechanism, i.e., trifluoromethanesulfonamide groups attack ketones to form initial azetane intermediates 54, the by-product 5 of trifluoromethanesulfonamide is released to form an aromatic hydrocarbon product 39.
Figure 5. An alternative 1,3-dicarbonyl nucleophile was used and an aromatization mechanism was proposed. Image source: Chem
As shown in Figure 6A, the authors synthesized C4 tertiary alkylated pyridinium 58 and 59 with high selectivity using the Minisci alkylation reaction developed by Baran et al., the latter of which yielded benzene 60 and 61 in high yields under the N-C bond exchange conditions developed here. In addition, since the pyridine C4-benzyl hydrogen atom may be rapidly eliminated to dihydropyridine upon trifluoromethanesulfonation, the authors attempted to study the C4-benzyldifluoromethylation, and the resulting structure is widely used in medicinal chemistry as a bioelectronic isosteric substitute for ether and carbonyl groups to enhance potency and physicochemical properties. Specifically, benzyl fluorination of 4-benzylpyridine 62 using the protocol proposed by Orellana et al. (Figure 6B) resulted in a smooth conversion of difluoride 64 to benzylfluoride 65 by N-C bond exchange (yield: 41%). Finally, the authors used a commercially available diethyl malonate-2-13C one-pot method to convert tert-butylpyridine to 1-13C-labeled benzoate 66 (yield: 94%, incorporation rate: >99%, Figure 6C), whereas the traditional synthesis method of ipso-13C-labeled benzene requires a cumbersome synthetic route.
Figure 6. Synthetic applications. Image source: Chem
summary
Prof. Michael F. Greaney's research group has developed a universal method for converting pyridine to benzene by N→C substitution using the ANRORC process, and obtained a variety of benzene derivatives in a one-pot method with good yields. The feasibility of this method is further demonstrated by the late modification of bioactive molecules and the synthesis of benzene molecules (including 1-13C labeled benzoates) that are difficult to prepare by other methods.
Synthesis of benzenes from pyridines via N to C switch
Aífe Conboy, Michael F. Greaney*
Chem, 2024, 10, 1940-1949, DOI: 10.1016/j.chempr.2024.05.004
Instructor introduction
Michael F. Greaney
https://www.x-mol.com/university/faculty/2412